Diabetes Ther (2010) 1(2):103-120.
DOI 10.1007/s13300-010-0008-2
REVIEW
The Management of Diabetic Ketoacidosis in Children
Arlan L. Rosenbloom
Received: October 28, 2010 / Published online: January 12, 2011
© The Author(s) 2011. This article is published with open access at Springerlink.com
0008-2
ABSTRACT
2
The object of this review is to provide
103 the definitions, frequency, risk factors,
pathophysiology, diagnostic considerations,
and management recommendations for diabetic
ketoacidosis (DKA) in children and adolescents,
and to convey current knowledge of the causes
of permanent disability or mortality from
complications of DKA or its management,
particularly the most common complication,
cerebral edema (CE). DKA frequency at the
time of diagnosis of pediatric diabetes is
10%-70%, varying with the availability of
healthcare and the incidence of type 1 diabetes
(T1D) in the community. Recurrent DKA rates
are also dependent on medical services and
socioeconomic circumstances. Management
should be in centers with experience and where
vital signs, neurologic status, and biochemistry
can be monitored with sufficient frequency to
Arlan L. Rosenbloom ()
Adjunct Distinguished Service Professor Emeritus,
Division of Endocrinology, Department of Pediatrics,
University of Florida College of Medicine, Gainesville,
Florida, USA. Address correspondence to: Children’s
Medical Services Center, 1701 SW 16th Ave, Gainesville,
FL 32608, USA. Email: rosenal@peds.ufl.edu
prevent complications or, in the case of CE, to
intervene rapidly with mannitol or hypertonic
saline infusion. Fluid infusion should precede
insulin administration (0.1 U/kg/h) by 1-2 hours;
an initial bolus of 10-20 mL/kg 0.9% saline is
followed by 0.45% saline calculated to supply
maintenance and replace 5%-10% dehydration.
Potassium (K) must be replaced early and
sufficiently. Bicarbonate administration is
contraindicated. The prevention of DKA at onset
of diabetes requires an informed community and
high index of suspicion; prevention of recurrent
DKA, which is almost always due to insulin
omission, necessitates a committed team effort.
Keywords: adolescents; cerebral edema;
children; complications; diabetic ketoacidosis;
fluid replacement; hypokalemia; management;
prevention; recurrent DKA
INTRODUCTION
Definition of Diabetic Ketoacidosis
Diabetic ketoacidosis (DKA) is biochemically
defined as a venous pH <7.3 or serum
bicarbonate concentration <15 mmol/L, serum
glucose concentration >200 mg/dL (11 mmol/L)
104 Diabetes Ther (2010) 1(2):103-120.

together with ketonemia, glucosuria, and Pathophysiology

ketonuria.1,2 Rarely, DKA may occur with normal
circulating glucose concentrations if there has
been partial treatment or with pregnancy.3,4 The
severity of DKA is determined by the degree
of acidosis:2
• Mild: venous pH >7.2 and <7.3, bicarbonate
<15 mmol/L
• Moderate: venous pH >7.1 and <7.2,
bicarbonate <10 mmol/L
• Severe: venous pH <7.1, bicarbonate
<5 mmol/L.
DKA is the result of a critical relative or
absolute deficit of insulin, resulting in
intracellular starvation of insulin-dependent
tissues (muscle, liver, adipose), stimulating
the release of the counter-regulatory
hormones glucagon, catecholamines, cortisol,
and growth hormone. The counter-regulatory
hormonal responses may also be the result of
stress-induced proinflammatory cytokines. 5
They stimulate lipolysis and proteolysis,

Figure 1. Pathophysiology of diabetic ketoacidosis. Absolute or relative insulin deficiency decreases glucose utilization in
insulin-sensitive tissues and promotes lipolysis. Energy deficiency in these tissues is a stress, stimulating counter-regulatory
hormones (glucagon, catecholamines, growth hormone, cortisol) and proinflammatory cytokines, which also stimulate these
hormones. The counter-regulatory hormones in turn enhance lipolysis and proteolysis, providing a substrate for hepatic
ketogenesis and hepatic and renal gluconeogenesis, all of which results in ketoacidosis, osmotic diuresis, dehydration, and
tissue hypoperfusion, adding lactic acidosis to the metabolic acidosis from accumulated ketones and loss of base in the urine.
Insulin deficiency

— Lipolysis ˜ Glucose utilization

Hepatic Starvation of insulin dependent

ketogenesis tissue (liver, fat, muscle)

Base loss Vomiting

Glucagon
Catecholamines
Growth hormone Proinflammatory
Cortisol cytokines

KETOACIDOSIS
Proteolysis & — hepatic gluconeogenesis

Osmotic diuresis HYPERGLYCEMIA

Hyperventilation Dehydration Tissue hypoperfusion

Lactic acidosis
Diabetes Ther (2010) 1(2):103-120.
hepatic and renal glucose production, and
hepatic oxidation of fatty acid to ketone
bodies. 6 Unlike during physiologic fasting,
absence of citric acid cycle processing of
glucose impedes the processing of these
ketones for energy (Figure 1).
Frequency and Risk Factors
DKA with New-Onset Diabetes
The frequency of new-onset diabetes presenting
as DKA varies widely by geographic region, and
correlates inversely with the regional incidence,
and therefore the level of awareness in the
community of pediatric diabetes. In Europe
this frequency varies from 11% to 67%. 7 In
Australia the frequency between 1985 and 2000
was 26%,8 and in New Zealand 63% in 1988/89
and 42% in 1995/96. 9 Children <5 years of
age are more likely to have DKA at diagnosis
as are those who are in social or economic
situations that do not permit ready access to
medical care.2,7-14 In patients from Colorado,
DKA was seen at onset in 28.4%; the odds ratio
for uninsured patients compared with insured
patients was 6.2, with significantly greater
severity in the uninsured group.12 Long-term
reductions in frequency of DKA at onset have
been reported following intensive education of
the medical and lay community.8-10 DKA at the
time of diagnosis has been estimated to occur
in as many as 25% of children with type 2
diabetes (T2D).2
It is not uncommon for previously
undiagnosed patients in DKA to have been
seen in physicians’ offices or emergency rooms
without adequate history and laboratory study
that could have made the diagnosis before
they became critically ill. A high index of
suspicion is particularly warranted for infants
and young children whose symptoms may
be nonspecific.
105
Recurrent DKA
Among 1243 patients in Colorado, the risk of
recurrent DKA was eight episodes per 100 patient
years; 20% of the patients accounted for 80%
of the episodes. The risk factors for recurrent
DKA were poor metabolic control or previous
episodes of DKA, female gender (peripubertal
or adolescent), psychiatric disorders including
eating disorders, difficult or unstable family
circumstances, limited access to medical
services, and insulin pump therapy. 12 Only
rapid- or short-acting insulin is used in pumps,
so that interruption of insulin delivery for
any reason rapidly leads to insulin deficiency.
In the 1970s and 1980s, the establishment
of treatment teams with intensive education
of families on sick day management and
24-hour availability demonstrated a profound
reduction in recurrent DKA, which is almost
invariably due to intentional omission of
insulin administration.15,16
Diagnosis and Initial Evaluation
Hyperglycemic hyperosmolar state (HHS) defined
as serum glucose >600 mg/mL (33 mmol/L),
serum osmolality >320 mOsm/L, and minimal
ketonemia/ketonuria, is being seen with
increasing frequency as the presenting indication
of T2D and may be associated with mild-to-
moderate acidosis from severe dehydration,
leading to confusion with DKA.17 Conversely,
patients with type 1 diabetes (T1D) may have
features of HHS, especially if they have been
satisfying their polydipsia with fluids containing
a high concentration of glucose.18 HHS has a
substantial mortality rate and requires aggressive
reconstitution of the circulatory volume.17-20
Body weight should be determined for
calculation purposes. Dehydration can be
estimated as 5% if there is reduced skin elasticity,
dry mucous membranes, tachycardia, and
106 Diabetes Ther (2010) 1(2):103-120.

Table 1. Estimating the level of dehydration.

Mild Moderate Severe
(infants ≤5%/ (infants 6%-10%/ (infants >10%-15%/
children ≤3 %) children 4%-6%) children >6%-10%)
Clinical state Alert Drowsy, irritable Lethargic/obtunded
Blood pressure Normal Normal Low
Heart rate Normal Increased/weak pulse Rapid/feeble pulse
Capillary refill Normal =2 seconds >3 seconds
Skin turgor Normal Tenting* Absent*
Eyes Normal Slightly sunken/reduced eyeball turgor Sunken/soft eyeballs
Oral mucosa/lips Moist Dry Very dry/parched
Urine output Normal Reduced Anuric
*Note that with severe hyperosmolality, skin and subcutaneous tissue are doughy rather than hypeoelastic.

Table 2. Glasgow Coma Scale (GCS). Reprinted with permission.2

Best verbal response
Best eye response Best verbal response (nonverbal children) Best motor response
1. No eye opening 1. No verbal response 1. No response 1. No motor response
2. Eyes open to pain 2. No words, only 2. Inconsolable, irritable, 2. Extension to pain
3. Eyes open to verbal incomprehensible sounds; restless, cries (decerebrate posture)
command moaning and groaning 3. Inconsistently consolable and 3. Flexion to pain
4. Eyes open spontaneously 3. Words, but incoherent* moans; makes vocal sounds (decorticate posture)
4. Confused, disoriented 4. Consolable when crying and 4. Withdrawal from pain
conversation† interacts inappropriately 5. Localizes pain
5. Orientated, normal 5. Smiles, oriented to sound, 6. Obeys commands
conversation follows objects and interacts
The GCS consists of three parameters and is scored between 3 and 15; 3 being the worst and 15 the best. One of the
components of the GCS is the best verbal response, which cannot be assessed in nonverbal young children. A modification of
the GCS was created for children too young to talk.
*Inappropriate words, no sustained conversational exchange.
†Attention can be held; responds in a conversational manner, but shows some disorientation.

deep breathing, and up to 10% with capillary
refill time greater than 3 seconds and sunken
eyes (Table 1). Calculations of fluid deficit are
commonly based on 10% dehydration, which
in most cases is a modest overestimate that does
not appear to have clinical significance. 21-22
The level of consciousness should be recorded
using the Glasgow Coma Scale (Table 2). 23
An initial venous blood sample should be
tested for glucose; electrolytes; pH; urea
nitrogen; creatinine; osmolality; ketones
or beta-hydroxybutyrate; hemoglobin and
hematocrit or complete blood count, while
keeping in mind that DKA is associated
with leukocytosis.
Osmolality can be measured or calculated
as: 2× (sodium [Na] + K) + glucose in millimoles
per liter (or glucose in mg/dL/18). The urine
should be checked for ketones. If there is any
possibility of delay in obtaining a serum K result,
Diabetes Ther (2010) 1(2):103-120.
Figure 2. Electrocardiographic patterns for hypo- and hyperkalemia.
Moderate hypokalemia
U-wave
Flat T-wave
Moderate hyperkalemia
Peaked T-wave
Wide, flat
P-wave
Wide QRS complex
electrocardiographic monitoring should be done
for K status.24,25 Severely ill patients should have
continuous electrocardiographic monitoring
using standard lead II or if the initial K level is
≤3 mEq/L or ≥6 mEq/L (Figure 2).26
Glycohemoglobin (HbA1c) concentration
will provide information about the severity and
duration of hyperglycemia in newly diagnosed
patients and can be compared with the previous
determination as an indicator of noncompliance
leading to the DKA in an established patient.
Measurement of serum-free insulin concentration
before the administration of insulin can confirm
an impression of failure to administer insulin as
the cause of recurrent DKA.27
The severely obtunded child will require
continuous nasogastric suction for the
prevention of pulmonary aspiration and may
require oxygen. Bladder catheterization should
be performed only in individuals who are unable
to void on demand; older patients may have an
atonic bladder with urinary retention requiring
initial catheterization, but not indwelling.28
107
Severe hypokalemia
Prominent U-wave
Severe hyperkalemia
Absent
P-wave
Very wide QRS complex
MANAGEMENT
Children with established diabetes, who are not
vomiting or severely ill, and whose caregiver
has been trained in sick day management,
can be managed at home or at an outpatient
facility, with appropriate supervision and
follow-up. 2,29-32 Children who are vomiting
and not severely ill may be managed with
intravenous (IV) fluids in an emergency
department and discharged to home if able
to take fluids orally following rehydration,
if venous pH is above 7.25, and telephone
follow-up can be assured. Children requiring IV
rehydration over an extended period need to be
admitted to a unit in which neurological status
and vital signs can be monitored frequently and
blood glucose levels measured hourly.2 Nursing
staff trained in monitoring and management of
DKA should be available and written guidelines
should be provided. 2,32 With severe DKA
(long duration of symptoms, compromised
circulation, depressed level of consciousness)
108
or if there are other factors increasing the risk
for cerebral edema (CE; age under 5 years, low
partial pressure of carbon dioxide [pCO2], high
serum urea nitrogen), an intensive care unit,
preferably pediatric, or an equivalent facility
is appropriate.2
Fluid and Insulin Replacement
Goals of Treatment with Fluid and Insulin
• Restore perfusion, which will increase
glucose uptake in the periphery, increase
glomerular filtration, and reverse the
progressive acidosis.
• A r r e s t k e t o g e n e s i s w i t h i n s u l i n
administration, which reverses proteolysis
and lipolysis while stimulating glucose
uptake and processing, thereby normalizing
blood glucose concentration.
• Replace electrolyte losses.
• Intervene rapidly when complications,
especially CE, occur.
Fluid Therapy
• Dehydration can be assumed to be 5%-10%
(50-100 mL/kg). As noted above, the degree
of dehydration is usually overestimated.
The severity of extracellular fluid (ECF)
contraction may be indicated by serum urea
and hematocrit concentrations.11 Serum Na
concentration is not reliable for determining
ECF deficit because of the osmotic effect
of hyperglycemia-induced dilutional
hyponatremia33,34 and the low Na content
of the elevated lipid fraction of the serum
in DKA. Corrected Na, ie for normal glucose
levels, can be estimated by adding 1.6 mEq
to the measured value for each 100 mg/dL
blood glucose above normal.33
• During the first 1-2 hours, 10-20 mL/kg 0.9%
sodium chloride (NaCl) should be provided
to restore peripheral perfusion.
Diabetes Ther (2010) 1(2):103-120.
• Maintenance can be calculated as 1000 mL
for the first 10 kg body weight + 500 mL for
the next 10 kg + 20 mL/kg over 20 kg or
1500 mL/m2 body surface area.
• The remainder of replacement after the
loading dose, based on 5%-10% dehydration,
and maintenance, can be distributed over
the subsequent 22-23 hours. While many
guidelines call for calculating replacement
over 48 hours, there is no evidence basis for
this being safer or more efficacious. Fluids
that have recently been administered orally
at home (if not vomited) and parenteral
fluids provided in the emergency room or
referring institution need to be incorporated
into the calculation.
• Except for severely ill and very young
individuals, oral intake should begin before
24 hours.
• While urinary output should be carefully
documented, urinary losses should not be
added to fluid requirements, except in the
presence of HHS.2,17,20
• After initial 0.9% NaCl bolus, rehydration/
maintenance should be continued with
0.45% NaCl. The measured Na can increase
to the level of the corrected Na during
rehydration as glycemia declines and then
decline to normal levels if the corrected
level was elevated.
• Continued use of 0.9% saline after the initial
resuscitation may result in hyperchloremic
metabolic acidosis.35,36
• To prevent unduly rapid decline in plasma
glucose concentration and hypoglycemia,
5% glucose should be added to the IV fluid
when the plasma glucose falls to 300 mg/dL
(17 mmol/L). An efficient method of
providing glucose as needed without
long delays entailed by the changing
of IV solutions is to have two IV fluid
bags connected, one containing 10%
Diabetes Ther (2010) 1(2):103-120.
dextrose and the appropriate Na and K
concentrations and the other with the same
salt concentrations but no dextrose, the
so-called “two bag system”.37
• K (40 mEq/L or up to 80 mEq/L as needed)
can be provided as half potassium chloride
(KCl), half potassium phosphate (KPO 4;
to replenish low phosphate levels and to
decrease the risk of hyperchloremia) or
as half KPO 4 and half K acetate (which,
like lactate, is converted to bicarbonate
to help correct acidosis) after serum K is
<6 mmol/L or urine flow is established.
Serum K concentration increases by
approximately 0.6 mEq/L for every
0.1 decrease in pH, so that the serum
K level does not reflect the large deficit
from diuresis and vomiting, ~5 mEq/kg
body weight. Both K and phosphate shift
markedly from intracellular to extracellular
compartments with acidosis and re-enter
cells rapidly with insulin-induced glucose
uptake and rehydration.26,38
• Bicarbonate administration is not
indicated in pediatric DKA. There is no
evidence that bicarbonate facilitates
metabolic recovery. Restoring circulatory
volume will improve tissue perfusion
and renal function, increasing organic
acid excretion and reversing lactic
acidosis. The administration of insulin
stops further synthesis of ketoacids and
reactivates the Krebs cycle, permitting
metabolism of ketoacids, and regeneration
of bicarbonate. Bicarbonate therapy
may cause paradoxical central nervous
system (CNS) acidosis, rapid correction
of acidosis can cause hypokalemia, the
additional Na can add to hyperosmolality,
and alkali therapy can increase
hepatic ketone production, potentially
slowing recovery.2
109
Insulin
• Insulin should be started after initial fluid
expansion. This provides a more realistic
starting glucose level.
• 0.1 U/kg/hour is given as a continuous
infusion, using a pump. Fifty units of regular
insulin are diluted in 50 mL normal saline
to provide 1 unit/mL.
• A bolus dose of insulin is not indicated and
may increase the risk of CE.39
• In some settings it may be necessary to
administer insulin subcutaneously. Studies
in adults have indicated no significant
difference in recovery time whether
insulin was administered intravenously,
intramuscularly, or subcutaneously after
the first couple of hours of treatment.40,43
A study of subcutaneous insulin in
children with DKA using a rapid-acting
insulin analog (lispro) provided a dose of
0.15 units/kg every 2 hours; there were
no significant differences from children
randomized to receive 0.1 unit/kg per
hour intravenously.44 The administration
of 0.1 unit/kg subcutaneously every hour
may be preferable and can be adjusted to
maintain blood glucose concentrations at
~180-200 mg/dL (10-11 mmol/L).
• Fluid expansion alone will have a dilutional
effect, lowering high blood glucose levels by
as much as 180-270 mg/dL (10-15 mmol/L).
With insulin infusion the rate of
glucose decline should be 50-150 mg/dL
(2.8-8.3 mmol/L/hour), but not >200 mg/dL
(11 mmol/L/hour). If serum glucose
values are not dropping adequately, the
insulin dose should be increased; this is
rarely necessary.
• If the blood glucose concentration falls
below 150 mg/dL (8.3 mmol/L) 10%
dextrose solution should be given and the
insulin dose reduced to 0.05 U/kg/hour if
110
glucose concentration is not sustained by
the 10% dextrose solution.
• Insulin should not be stopped; a continuous
supply of insulin is needed to prevent
ketosis and permit continued anabolism. If
the patient demonstrates marked sensitivity
to insulin, the dose may be decreased to
0.05 units/kg/hour, or less, provided that
metabolic acidosis continues to resolve.
• Persistent acidosis, defined as bicarbonate
value <10 mmol/L after 8-10 hours of
treatment, is usually caused by inadequate
insulin effect. Insulin dilution and rate of
administration should be checked, and
a fresh preparation made. Too dilute a
solution may enhance insulin adherence
to the tubing. If insulin is being given
by subcutaneous injection, inadequate
absorption may be occurring. Rare causes
of persistent acidosis include lactic
acidosis due to an episode of hypotension
or apnea or inadequate renal handling of
hydrogen ion as a result of an episode of
renal hypoperfusion.28
Monitoring
Successful management and early intervention
for complications requires close monitoring. A
flow chart should be maintained to document
all relevant incidents regarding the patient’s
condition. 28 Minimal monitoring frequency
recommendations include vital signs and
neurologic checks hourly; blood glucose
hourly; venous blood gases every 2 hours for
6 hours, then every 4 hours; Na, K, and ionized
calcium every 2 hours for 6 hours, then every
4 hours; magnesium and phosphorus every
4 hours; basic metabolic profile at admission
and then every morning. These minimum
requirements should be adapted to the
situation; for example, more frequent (hourly)
Diabetes Ther (2010) 1(2):103-120.
K measurements may be indicated, along
with electrocardiogram (ECG) monitoring
depending on the initial K value, 24,25 or more
frequent neurologic and vital sign checks
(20-30 minutes) if there is a concern about the
patient’s mental status.28
Ketonuria should not be used as a measure
of improvement. The dip sticks used to measure
ketones react with acetoacetate. Concentrations
of beta-hydroxybutyrate are much higher than
those of acetoacetate and will be converted to
acetoacetate during successful treatment of
the DKA, resulting in sustenance or increase
of urinary ketone concentration. Laboratory
measurement or the use of a bedside fingerstick
sample monitor for beta-hydroxybutyrate will
avoid this problem.
Transition
• IV fluids can be stopped 1-2 hours after
substantial consumption of oral fluids
without vomiting.
• Subcutaneous insulin injection can be
started when IV fluids are no longer
needed. Presupper or prebreakfast time is
most convenient for starting or restarting
intermediate- or long-acting insulin. Before
then, rapid-acting or regular insulin 0.25 U/kg
subcutaneously can be given every
~6 hours, and the insulin infusion stopped
60-120 minutes after the first subcutaneous
dose of regular insulin or 60 minutes after a
rapid-acting insulin analog.
• Patients should not be kept in the hospital
simply to adjust insulin dosage because food,
activity, and psychosocial environment are
not normal in the hospital setting. Therefore,
insulin requirements will not be particularly
informative for home management.
• Established patients with DKA can resume
their usual home dose of insulin.
Diabetes Ther (2010) 1(2):103-120.
COMPLICATIONS OF DKA OR ITS
TREATMENT
Most of the diabetes-related morbidity and
mortality in childhood T1D can be attributed
to complications of DKA. 2 Mortality risks
for each episode of DKA have been reported
from the United States (0.15%), 45 Canada
(0.18%-0.25%), 46,47 and the United Kingdom
(0.31%). 48 CE accounts for 60%-100% of
this mortality. 45,50 Other causes of death or
disability with DKA include hypokalemia,
hypophosphatemia, hypoglycemia, other
intracerebral complications, peripheral venous
thrombosis, mucormycosis, rhabdomyolysis,
acute pancreatitis, acute renal failure,
sepsis, aspiration pneumonia, and other
pulmonary complications. 2 Prevention of
hypokalemia was noted in the section of
fluid therapy. Hypophosphatemia can cause
progressive muscle weakness and death due to
cardiorespiratory arrest days after metabolic
recovery from DKA and can be prevented
by administration of half of the K as KPO 4;
administration of all the K as KPO 4 can result
in hypocalcemia.51,52
Renal Failure
Renal failure is a common complication and
cause of mortality with HHS, necessitating early
consideration of dialysis,17 but is extremely rare
with pediatric T1D.
Peripheral Venous Thrombosis
Central venous catheter (CVC) placement was
associated with deep venous thrombosis (DVT)
in four of eight children with DKA,53 and in
three of six pediatric intensive care unit (PICU)
patients with DKA who required femoral CVC
(out of 113 DKA/PICU patients). 54 The PICU
111
patients were under 18 months of age and
required long-term heparin therapy for persistent
leg swelling; in contrast, seven comparably aged
patients with shock who had femoral CVC for
longer periods of time than the DKA patients
had no episodes of DVT. This suggested that DKA
is associated with a thrombotic diathesis beyond
that which is attributable to dehydration.
In the absence of DKA, coagulation factor
abnormalities have not been demonstrated in
children with diabetes,55 but von Willebrand
factor activity remains elevated at 120 hours
following admission for DKA.56 Thus, DKA and
its treatment may promote a prothrombotic
state and activation of vascular endothelium,
predisposing to thrombosis.
More than 50% of children who have venous
thromboses will carry a genetic thrombophilic
defect, and two-thirds of such defects will be a
mutation in the factor V gene referred to as factor
V Leiden.57 Massive arterial thrombosis resulting
in unilateral below-the-knee amputation has
been reported in a 12-year-old female patient
with a heterozygous factor V Leiden mutation
and a 2-year history of poorly controlled T1D
who was not in DKA.58
Pancreatitis
Acute pancreatitis is a recognized complication of
DKA in adults and in new-onset T2D with HHS17
but is unusual in childhood T1D. Serum levels
of amylase and lipase were commonly elevated
in 50 children with DKA at onset of T1D. 59
The amylase elevation is of salivary origin. The
serum lipase level was directly associated with
the degree of acidosis, and acute pancreatitis
was demonstrated by abdominal computed
tomography (CT) in one of the patients who had
persistent abdominal pain.59 Acute pancreatitis
must be considered with abdominal pain that
does not resolve with correction of acidosis.
112
Rhabdomyolysis
Rhabdomyolysis is a common complication of
HHS and is associated with renal failure.17 It
occurs with DKA, but in the absence of HHS is
not associated with mortality. Risk factors include
severe hyperglycemia, high osmolality, and
hypophosphatemia. A 15-month-old was added
to the few reported pediatric cases in 2003.60 The
occurrence of rhabdomyolysis in a 27-month-old
patient 25 years earlier led to a chart review of
133 children admitted with new-onset diabetes,
of whom 12 had orthotolidine reactions, which
detect myoglobin in the urine.61
Mucormycosis
This acute, rapidly progressing, and often fatal
facultative fungal infection occurs in young
patients with diabetes who have chronically
poor glycemic control and ketoacidosis. The
principal locus may be rhinocerebral, pulmonary,
cutaneous, gastrointestinal, or in the CNS,
or it may be disseminated. In a series of five
patients, the sole survivor had severe neurologic
disability; risk factors were African American
race and history of poor compliance (poor clinic
attendance, risk-taking behaviors, and high rate
of hospital admission).62
Cerebral Edema
In 1967, two teenage patients were reported
with fatal CE and only three others were
identified from the literature with a similar
clinical history.63 In the subsequent 13 years,
only 13 more cases were reported.64 In the next
10 years the total reported cases reached 40 and
in 1990 an additional 29 were added in one report
and 11 in another.49,65 Subsequently, another
~160 cases have been added. These reports have
provided incidence data and have emphasized
Diabetes Ther (2010) 1(2):103-120.
the idiosyncratic nature of the occurrence of CE
and the absence of iatrogenic causation.66,67
Frequency
A 3-year United Kingdom population-based
study yielded an incidence of 0.7% overall,
with a marked discrepancy between the newly
diagnosed, 1.2%, and established patients,
0.4%.68 A higher incidence of 4.3% in newly
diagnosed, 1.3% in established patients, and
2% overall was reported from Australia. 8 The
North American multicenter study reported an
incidence of 0.9% for CE without differences
between new-onset and established patients.50
In a prospective surveillance study in Canada of
patients <16 years of age with DKA, there were
13 verified cases of CE, for a rate of 0.51% of
episodes of DKA.47 Variations in case definition
and referral patterns likely explain some of these
differences in the reported frequencies of CE.
Morbidity and Mortality
Earlier reports may reflect biased fatality and
residual morbidity data and later recognition
than more recent population-based observations.
Appropriate intervention was also less frequent
in these earlier-reported and litigated cases.
The first extensive series, in 1990, analyzed
69 cases, including 40 that were previously
published, and found a case fatality rate of 64%
overall. Survival without disability was noted
in 14%, with disability that did not preclude
independence in 9%, and severe disability or
vegetative state in 13%. Among those who were
treated before respiratory arrest, even if this was
at the gasping stage, case fatality was only 30%,
with 30% surviving without disability, 26% with
disability not precluding independence, and
13% with severe disability or vegetative state.49
Although the intervention in these cases was
often inadequate and after severe neurologic
compromise, the outcome with treatment is
Diabetes Ther (2010) 1(2):103-120.
similar to those in contemporary population-
based studies. There have been a few case reports
of CE developing before initiation of treatment
of DKA and a report from Canada indicated that
19% of cases of CE were present before treatment
was undertaken.47,49,50,68
Risk Factors
Young children, especially <5 years of age, are
at increased risk for the development of CE.
This may reflect the more rapid deterioration
in this age group and greater delay in diagnosis
because of nonspecificity of symptoms. The
younger brain might also be more susceptible to
metabolic and vascular changes associated with
DKA. Severity of acidosis, degree of hypocapnia,
and elevated serum urea nitrogen, indicators of
severity of ketoacidosis and dehydration, have
been noted to be risk factors.2 Although Na
bicarbonate administration was significantly
associated with the development of CE in
one population-based case-control study, 50
this association may simply reflect the greater
severity of ketoacidosis that was not adequately
controlled for in the case-control design, rather
than an effect of the bicarbonate.69
CE associated with DKA is rarely seen
beyond the pediatric age group (0-21 years)67
or in adult patients with HHS, despite rapid
rehydration and restoration of normal
glycemia.70 In several studies increased risk of
CE has been associated with a failure of serum
Na concentration to increase appropriately
during treatment for DKA. This may be because
those who are in the early, presymptomatic
stages of CE experience changes in the brain
that result in dysregulation of antidiuretic
hormone secretion.50,71 The absence of evidence
of associations between volume or tonicity of
fluids or the rate of change in serum glucose
and risk of CE indicates that this might be
the result of altered renal Na handling due to
113
cerebral injury, rather than the type or rate of
fluid administration.2,47,49,65,71
In the 61 children with CE from a
North American multicenter study, worse
outcomes occurred in those with greater
neurologic depression at the time of diagnosis
of CE and with higher initial serum urea
nitrogen concentrations. 50,72 Intubation and
hyperventilation to a pCO2 of <22 mmHg also was
associated with worse outcome, dictating the need
for caution in hyperventilating patients.2,72
Mechanisms
CE refers to an increase of cerebral tissue water
causing an increase of tissue volume. 73 The
edema may be vasogenic, due to breakdown of
the blood-brain barrier, such as around a tumor
or with trauma; cytotoxic, from poisoning or
metabolic derangement; or osmotic, as occurs
with hyponatremia. Neither the cause nor the
location of the fluid in the swollen brains of
children with DKA is known. The mechanism
is likely to be complex, and it may not be the
same in all affected individuals, as reflected
by the time of onset and the brain imaging
findings. The time of onset is distributed in a
bimodal fashion, with approximately two-thirds
of patients developing signs and symptoms in
the first 6-7 hours and the rest from 10-24 hours
after the start of treatment, with the early-onset
individuals tending to be younger.50,71,72
Initial brain CT undertaken 2-44 hours after
the diagnosis of CE found 39% with no acute
abnormalities visible, and this did not differ
significantly between early and late-onset
subjects. Twenty-six percent had diffuse edema,
which was also similar between early and late
onset. Three of the eight with diffuse edema
also had hemorrhages, and 17% of the entire
group had only subarachnoid or intraventricular
hemorrhage. Five subjects had focal brain injury
in the mesial basal ganglia and thalamus, the
114
periaqueductal gray matter, and the dorsal
pontine nuclei (22%). These localized injuries
were only in the early-onset patients. They were
not an artifact of the time that the studies were
performed, and thus, truly reflect what appear to
be widely varying pathology in the brain leading
to the syndrome that is referred to as “idiopathic
CE”. 71 The observation that approximately
40% of initial brain imaging studies in
children who have CE are normal emphasizes
that CE is a clinical diagnosis requiring the
initiation of treatment before imaging studies
are undertaken.
Monitoring
Because treatment modification has not
prevented CE and with the strong evidence that
early administration of mannitol prevents brain
damage and death from this complication, Muir
et al. developed a model for early detection.71
Diagnostic criteria were abnormal motor or
verbal response to pain; decorticate or decerebrate
posture; cranial nerve palsy (especially III,
IV, VI); and abnormal neurogenic respiratory
pattern (eg, grunting, tachypnea, Cheyne-
Stokes, apneustic). Major criteria were altered
mentation/fluctuating level of consciousness;
sustained heart rate deceleration (decline more
than 20 per minute) not attributable to improved
intravascular volume or sleep state; and age-
inappropriate incontinence. Minor criteria
were vomiting following initial treatment and
its cessation, if present at admission; headache
(recurrent and more severe than on admission);
lethargy or not easily aroused from sleep; diastolic
blood pressure greater than 90 mmHg; and age
<5 years. The system allowed 92% sensitivity and
96% specificity for the recognition of CE early
enough for intervention, using one diagnostic
criterion, two major criteria, or one major plus two
minor criteria. This means that five youngsters
will be treated for CE to prevent brain damage
Diabetes Ther (2010) 1(2):103-120.
or death in one patient, a reasonable proposition
considering the alternative of waiting for more
stringent criteria to be met.
Treatment
Improvement has been consistently observed
with administration of IV mannitol in a dosage
of 1.0 g/kg over 20 minutes with repeat as
necessary in 1-2 hours and associated measures
as soon as CE is suspected, especially before
respiratory arrest.2,49,50,65 Intervention includes
reduction in the rate of fluid administration
and elevation of the head of the bed. Although
early intervention with mannitol treatment has
improved outcome, it is difficult to determine
to what degree, because increased recognition
of the problem has undoubtedly led to less
stringent case definition. The application of
criteria developed by Muir et al., when applied
to a series of 69 consecutive cases thought to be
uncomplicated and experiencing full recovery,
yielded three (4.3%) who would have been
appropriately treated with mannitol according
to these criteria.71 This is remarkably close to the
percentage of DKA patients treated as CE in a
recent report of 18 years experience.76
Mannitol lowers the hematocrit and blood
viscosity, improving cerebral blood flow (CBF)
and oxygenation, red cell deformability, and
vasoconstriction in areas of the brain with
intact autoregulation. It may also improve
autoregulation from the effects on CBF and
oxygenation, and has direct osmotic effects with
reduction in extracellular free water. Intensivists
frequently express concern about the use of
mannitol because of their experience with the
risk of rebound edema and renal failure when
mannitol is used over an extended period.
However, there are no reports of complications
of mannitol use in this acute situation.
Hypertonic saline (HS) has become the standard
for treating acute intracranial hypertension in
Diabetes Ther (2010) 1(2):103-120.
head injury and following surgical procedures
in the supratentorial region and in these
circumstances has been considered at least as
effective as mannitol.75-79 HS for treatment of CE
in DKA was initially described in a 13-year-old
female patient who developed a severe headache
20 minutes after the start of treatment and who
had CT evidence of diffuse CE with transtentorial
herniation. She continued to deteriorate despite
mannitol treatment and was given 5 mL/kg of
3% saline rapidly; she awoke with recovered
neurologic function within 5 minutes.80 The use
of 5-10 mL/kg 3% saline in patients who have not
responded adequately to mannitol infusion of a
dose of 1 g/kg appears justified.
Intubation should be reserved for those
with respiratory compromise, but should not
be undertaken simply because of the diagnosis
of CE. Aggressive hyperventilation was a
significant risk factor for poor outcome in the
study of Marcin et al.,72 similar to detrimental
effects reported in head trauma and high-
altitude exposure.81,82
Intracerebral Complications other than CE
Approximately 10% of all instances of
neurologic collapse during ketoacidosis can
be attributed to intracerebral complications,
with or without associated edema, but by
definition not idiopathic CE.2 The causes include
subarachnoid hemorrhage, 49 basilar artery
thrombosis,49 cerebral venous thrombosis,83,85
meningoencephalitis, 86 and disseminated
intravascular coagulation.87,88
PREVENTION OF DKA
Prevention of DKA at onset is most dramatically
demonstrated when early diagnosis is made
through genetic and immunologic screening of
high-risk children.7,15 For the general population,
115
an example has been provided by the Italian
School and Physician Awareness Program
directed at 6-14-year-olds, which reduced the
rates of new-onset DKA from 78% to nearly 0%
over 6 years10 Materials used in this effort are
available online.89
In the 1970s, a comprehensive approach
involving outreach clinics, frequent routine and
emergency telephone contact, and a camping
program supported by state funding for children
with special healthcare needs dramatically
reduced recurrent DKA episodes. Private
patients in the program had a reduction in
hospital admission days from preintervention of
2.8/patient/year to 0.3 and in the second
year to 0. The children sponsored by the state
program had a reduction from 4.9/patient/year
to 1.8 and in the second year to 0.9.15
Patients with compliance problems account
for a disproportionate number of recurrent
DKA episodes. In the UK surveillance study,
4.8% of patients accounted for 22.5% of all
episodes68 and as noted above, 20% of patients
in Colorado accounted for 80% of recurrent DKA
episodes.14 The principal immediate reason for
the recurrent DKA in children and adolescents
is insulin omission, reflected in low or absent
levels of free insulin.27 The necessity for assuring
administration of insulin by responsible adults
is critical.
CONCLUSION
DKA is the result of absolute or relative
deficiency of insulin in combination with
exuberant secretion of counter-regulatory
hormones (glucagon, catecholamines, cortisol,
growth hormone) resulting in blockade of
glucose utilization in insulin-sensitive tissues
(liver, fat, muscle) and a cascade of derangement
progressing to ketoacidosis and dehydration.
Much new-onset DKA can be prevented by
116
increased awareness of early signs and symptoms
of diabetes and, in principle, almost all
recurrent DKA is preventable by informed sick
day management, recognition of psychosocial
problems leading to insulin omission, and
careful monitoring of insulin pump function.
Management of DKA should occur in centers
with treatment experience and monitoring
capability. Fluid replacement begins with 0.9%
saline to restore circulation and subsequent
0.45% saline for maintenance and replacement
of 5%-10% dehydration, according to severity
indicators. Whether levels of serum K are normal
or elevated, there will be a total K deficit that must
be dealt with early and sufficiently. Bicarbonate
administration is neither necessary nor safe.
Mannitol or hypertonic saline should be at the
bedside, for rapid intervention as indicated for
CE, the most common serious complication of
DKA. Other complications include hypokalemia,
hypophosphatemia, hypoglycemia, intracerebral
complications other than CE, peripheral
venous thrombosis, mucormycosis, aspiration
pneumonia, rhabdomyolysis, acute pancreatitis,
and acute renal failure. Among questions that
need to be addressed regarding DKA in children
and adolescents are whether feasible and cost-
effective methods can reduce the frequency of
new-onset and recurrent DKA, what characterizes
optimal fluid replacement therapy, how effective
proposed monitoring and intervention criteria
are in the reduction of CE morbidity and
mortality, and whether hypertonic saline is as or
more effective than mannitol in the treatment
of CE.
Key points
• Treatment of DKA requires first and foremost
fluid resuscitation with 0.9% saline, followed
by replacement for 5%-10% dehydration,
depending on severity, and maintenance
Diabetes Ther (2010) 1(2):103-120.
with 0.45% saline, and early and adequate
K replacement.
• Insulin should not be given as a bolus, but
infused after the initial fluid resuscitation in
a dose of 0.1 U/kg of body weight/hour.
• Bicarbonate infusion is contraindicated in
pediatric DKA.
• CE is the most common serious complication,
requiring careful neurologic and vital sign
monitoring and early intervention with
mannitol or hypertonic saline infusion.
ACKNOWLEDGMENTS
The author has no conflicts of interest to declare.
A.L.R. is the guarantor for this article, and takes
responsibility for the integrity of the work as
a whole.
Open Access. This article is distributed
under the terms of the Creative Commons
Attribution Noncommercial License which
permits any noncommercial use, distribution,
and reproduction in any medium, provided the
original author(s) and source are credited.
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